Obesity affects nearly half of the adult U.S. population and represents the single most important risk factor for development of insulin resistance and diabetes. Obesity is associated with a state of chronic, low-grade inflammation in insulin target-tissues such as the liver and adipose tissue. At the cellular level, macrophages appear to play a major role in promoting obesity-related inflammation. During the development of insulin resistance, resident liver macrophages (Kupffer cells) and monocytes that are recruited to the liver from the bone marrow (myelopoiesis) become activated, and release cytokines and chemokines. These molecules contribute to insulin resistance and to the development of type 2 diabetes (T2D). More importantly, abrogation of these macrophage-driven inflammatory mediators attenuates the development of insulin resistance/diabetes during obesity. Unfortunately, the factors that oppose these inflammatory macrophage-derived mediators have not been identified. Nitric oxide and endothelial nitric oxide synthase (eNOS or Nos3) are well-established contributors to vascular homeostasis. Nevertheless, loss of Nos3 appears to result in metabolic derangements that contribute to insulin resistance. More specifically, a reduction in Nos3-derived NO during obesity precedes the development of insulin resistance and genetic deletion of Nos3 (Nos3-/- mouse) is associated with both systemic and hepatic insulin resistance. Moreover, pharmacologic strategies that restore NO bioavailability during obesity (e.g. PDE5 inhibition) and genetic strategies that increase NO production (e.g. Nos3 overexpression) restore insulin sensitivity in mice. Our laboratory and others have long attributed the salutary metabolic effects of Nos3 to endothelium-mediated improvement of blood flow that increases delivery of nutrients to insulin-sensitive tissues such as liver, muscle, and adipose tissue, thereby facilitating nutrient utilization or storage and maintaining metabolic homeostasis. However, recent work from our laboratory suggests that, during obesity, macrophage Nos3-not endothelial Nos3-preserves metabolic homeostasis in a cell-autonomous manner by reducing macrophage production of inflammatory cyto/chemokines. Here we propose a novel model in which NO produced by macrophage Nos3 acts as a physiological brake on macrophage activation. During obesity, we propose that a reduction in macrophage-derived NO releases this brake, increasing macrophage activation and promoting insulin resistance. We propose the novel hypothesis that macrophage Nos3/NO is required to maintain hepatic insulin sensitivity through its effects on macrophage activation and myelopoiesis, and that the loss of these effects of NO leads to obesity-associated hepatic insulin resistance. If this hypothesis is correct, the translational significance will be considerale because therapeutic options that increase NO bioavailability are already available.